Combination Particles Containing Salmeterol Xinafoate and Fluticasone Propionate: Formulation and Aerodynamic Assessment

Abstract

A precipitation process is used to produce combined particles consisting of two antiasthmatic drugs: salmeterol xinafoate and fluticasone propionate. To control the crystallisation of these particles, a micromixer is used to mix solvent and antisolvent flow. To produce particles in the respirable range, crystal growth inhibitors are added to the antisolvent flow. The obtained suspension is spray-dried afterwards to get a dry powder which can be further processed into inhalation drug products. It is found that a combination of polysorbate 80 and hydroxypropylmethyl cellulose (HPMC) represents the best excipient combination. It is supposed that the smaller molecule polysorbate rapidly stabilises the particle surface and with this inhibits crystal growth, whereas HPMC is observed to produce spherical particles during the spray-drying process acting as lubricant and dispersion-modifier. The processed particles show a needlelike habit and, therefore, tend to form aggregates. When dispersed from an inhaler device, they are only moderately disaggregated. The deposition of the single drugs salmeterol xinafoate and fluticasone propionate on the stages of the NGI shows a very uniform distribution, indicating that both drugs are evenly dispensed, with an FPF of about 22% for the combined particles which corresponds to the deposition of the marketed product.